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Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Department of Physiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocardial actions of the vasodilator
peptide adrenomedullin (ADM) in the intact animal are unknown. Negative
and positive inotropic actions have been reported in ex vivo
experiments. Myocardial and load-altering actions of ADM in dogs before
and after development of heart failure were studied. With
controlled heart rate (atrial pacing) and after 
-blockade, ADM
was administered to five normal dogs in doses of 20 ng · kg
1 · min1 iv, 100 ng · kg1 · min1 iv, and 200 ng · kg1 · min1 into the left
ventricle (LV). LV peak systolic pressure and end-systolic volume
decreased with each dose of ADM. End-systolic pressure decreased with
the two higher doses. At the highest dose, arterial elastance and the
time constant of LV isovolumic relaxation (
) decreased, and LV
end-systolic elastance (Ees) increased. LV
end-diastolic pressure and volume were unchanged. In five additional
normal dogs receiving only the highest dose of ADM (200 ng · kg1 · min1 intra-LV), to
control for increased heart rate and sympathetic activation observed
with the cumulative infusion, ADM produced arterial vasodilation but no
change in Ees or . In four dogs with
pacing-induced heart failure, ADM (200 ng · kg1 · min1 intra-LV) was
without effect on , Ees, and systolic or
diastolic pressure and volume. In vivo, ADM appears to be a selective
arterial dilator without inotropic or lusitropic effects. The
vasodilatory actions are attenuated in heart failure.
inotrope; hemodynamics
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ADRENOMEDULLIN (ADM) is a recently discovered 52-amino acid peptide that circulates in human plasma (17). Infusion of this peptide results in vasodilation and natriuresis in vivo (11, 21). Plasma concentrations of ADM are increased in a variety of cardiovascular disorders, including hypertension and heart failure (6, 12, 15, 16). These findings suggest that ADM may play a role in the regulation of cardiovascular homeostasis.
The actions of ADM are thought to be mediated, in part, through the second-messenger cAMP and through effects on intracellular calcium homeostasis (9, 24). Therefore, it is possible that ADM may have inotropic effects. In vitro studies of the myocardial effects of ADM have yielded conflicting results, with experiments in isolated hearts showing a cAMP-independent positive inotropic effect and studies in isolated myocytes showing a negative inotropic effect (8, 28, 29). The effect of ADM on left ventricular (LV) function and the potential therapeutic role of ADM as a vasodilator or inodilator in vivo have not been defined.
To date, no study has directly assessed the effects of ADM on myocardial contractility in vivo in either normal or heart-failure states. Although studies in intact animals have shown an increase in cardiac output and an increase in the maximum rate of change of aortic flow with ADM administration, changes in these variables may be influenced by changes in loading conditions or heart rate rather than by direct positive inotropic effects (3, 22). In addition, the effect of ADM on diastolic myocardial function has not been studied.
This study was designed to document for the first time the effects of ADM infusion on myocardial contractility and diastolic function in conscious normal dogs and dogs with experimental heart failure. A range of doses was used to produce pathophysiological and pharmacological plasma concentrations. Because ADM may possess vasodilatory and inotropic effects, we utilized the end-systolic pressure-volume relationship to assess myocardial effects, as it is a relatively load-insensitive measure of myocardial contractility (14, 25). We hypothesized that ADM would have both vasodilator and positive inotropic effects.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiments were performed in male mongrel dogs. Dogs weighed between 18 and 24 kg and were fed standard dog chow (Lab Canine Diet 5006; Purina Mills, St. Louis, MO); dogs had free access to drinking water. The study was approved by the Institutional Animal Care and Use Committee of the Mayo Clinic and was conducted in accordance with the Animal Welfare Act.
Instrumentation. Dogs were anesthetized with Pentothal Sodium (20 mg/kg) and isoflurane (0.5-2.5%) and were ventilated with supplemental oxygen. A left lateral thoracotomy was performed, and the pericardium was widely opened. A solid-state micromanometer pressure transducer (Konigsberg Instruments, Pasadena, CA) and a silicon fluid-filled catheter for transducer calibration were inserted through the LV apex. Piezoelectric ultrasound dimension crystals (Triton Technology, San Diego, CA, or Sonometrics, London, ON, Canada) were implanted on opposing anterior and posterior endocardial surfaces of the LV to measure the internal short-axis dimension and at the basal epicardial and apical endocardial surface to measure the LV long-axis dimension. Hydraulic occluders were placed on the proximal superior and inferior vena cavae (In Vivo Metrics, Heladsburg, CA). A pacing wire was sutured to the left atrial free wall for use in controlling heart rate during the acute experiments. In dogs used for the heart-failure experiments, a screw-in epicardial pacing lead was placed on the right ventricular (RV) free wall, and a programmable cardiac pacemaker (model 8329 or 5985; Medtronic, Minneapolis, MN) was implanted subcutaneously for chronic RV pacing.
Data collection. Studies were performed after full recovery from the thoracotomy (10-14 days) in the normal dogs and after the pacing protocol was completed in heart-failure animals. All studies were undertaken with the dogs awake and standing quietly in a sling. The LV fluid-filled catheter was connected to a calibrated pressure transducer, and the signal from the micromanometer was adjusted to match that of the fluid-filled catheter. LV dimensions were measured by use of the implanted ultrasonic crystals (3 MHz) and a sonomicrometer. The analog signals of pressure and dimension were processed with an analog-to-digital online data acquisition and control system that allowed online display of all parameters (CA Recorder version 1.1; Data Integrated Scientific Systems, Pinckney, MI).
Experimental protocol. Five normal dogs were studied initially. These normal dogs were given propranolol at 2 mg/kg intravenously (but no other premedication) and paced from the left atrium at ~20 beats/min above their intrinsic heart rate to block effects of vasodilator-induced reflex sympathetic activation and to control heart rate throughout the experimental protocol.
Fifteen minutes after the administration of propranolol and the commencement of atrial pacing, baseline recordings were made. Three steady-state recordings, each of 20-s duration to account for respiratory variation, were made over ~5 min. After completion of the steady-state recordings, at least three sets of variably loaded pressure-volume loops were generated by transient occlusion of the cavae. Hemodynamic variables were allowed to return to baseline between each caval occlusion. After collection of the baseline data, human ADM-(1---52) (Phoenix, Mountain View, CA) was infused at three different doses, each for 30 min: 20 ng · kg1 · min1 intravenously, 100 ng · kg1 · min1 intravenously, and
finally 200 ng · kg1 · min1 via the
LV fluid-filled catheter. The final dose administered directly into the
LV was designed to produce marked elevation of intracoronary ADM
concentrations. At the end of each 30-min infusion, steady-state and
variably loaded pressure-volume loop recordings were repeated as
described above.
Venous blood samples were collected for measurement of plasma ADM and
cAMP concentrations at baseline and at the end of each ADM dose. Venous
blood samples for measurement of plasma norepinephrine and epinephrine
were collected at baseline and at the end of the final ADM dose.
The highest dose of ADM was associated with an increase in plasma
norepinephrine and an increase in heart rate above the atrial pacing
rate, suggesting reflex sympathetic activation in response to decreases
in arterial pressure. Also, the cumulative infusion of ADM had
decreased LV end-systolic pressure dramatically, such that the
end-systolic pressure-volume relationship before ADM and after the last
dose of ADM showed relatively little overlap. These observations make
interpretation of any inotropic and lusitropic effects at the highest
dose of ADM difficult. To evaluate potential inotropic or lusitropic
responses of the highest dose of ADM in the absence of reflex
sympathetic activation and at more similar systolic pressures, five
additional normal dogs were studied with only the highest dose of ADM
(200 ng · kg1 · min1 intra-LV over
30 min) 15 min after administration of propranolol. The decrease in the
total dose of ADM and the lack of a prolonged period since propranolol
administration were designed to reduce the chance that reflex
sympathetic stimulation was responsible for changes in LV function.
Data collection was identical to the initial study except that only one
dose of ADM was used.
Heart failure was then induced in these five dogs by rapid RV
pacing (240 beats/min for 3 wk). This pacing protocol produces a model
of severe heart failure (2). For technical reasons, data
could only be collected on four dogs in heart failure. At the
completion of the pacing protocol, ventricular pacing was stopped, and
the dogs were studied with infusion of ADM (200 ng · kg1 · min1) into the LV and
with atrial pacing to control heart rate but without administration of
propranolol. Data were collected at baseline and end of ADM infusion in
the same manner as in the previous studies.
Data analysis. Steady-state recordings were averaged over the 20-s recording period to account for respiratory variation.
LV volume was calculated as a modified ellipsoid model with the use of the following equation
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). The time from peak negative dP/dt
to 5 mmHg above LV end-diastolic pressure was fit to an exponential
equation: P = P0et/
, where P is LV
pressure, P0 is LV pressure at peak negative
dP/dt, t is time, and is a constant
determined by the data (23).
Only caval occlusions that produced a fall in end-systolic pressure of
at least 30 mmHg were analyzed. Premature beats and two subsequent
beats were excluded from the analysis. The LV end-systolic pressure and
volume data during the fall in LV pressure, caused by each caval
occlusion, were fit by use of the least squares technique to the
equation Pes = Ees(Ves 
V0),
where Pes is end-systolic pressure,
Ees is slope of the linear end-systolic
pressure-volume relationship (representing the LV end-systolic
elastance), Ves is volume at end systole, and
V0 is intercept with the volume axis. The slope of the
end-systolic pressure-volume relationship (Ees)
is sensitive to changes in contractile state but relatively insensitive
to changes in loading conditions.
Plasma assays.
Venous blood samples were collected into EDTA and immediately placed on
ice. After centrifugation at 2,500 rpm for 10 min, the plasma was
decanted and stored at 20°C until analysis.
Statistics. All data are presented as means ± SE. Comparisons within the multiple-dose normal group were made by one-way ANOVA for repeated measures followed by a post hoc analysis with Dunnett's test or a test for linear trend. Comparisons within and between the single-dose normal and heart-failure groups were made with the use of t-tests. Statistical significance was accepted as P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All dogs tolerated the protocol, and all results are included in the analyses.
Normal dogs with multiple doses of ADM.
Steady-state hemodynamic measurements at baseline and at the end of
each ADM dose are shown in Table 1.
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, the time constant of LV isovolumic relaxation, decreased with the highest dose of ADM.
Ees was significantly increased with the highest
dose of ADM but was unchanged by the lower infusion doses.
V0 increased with the highest dose of ADM. Figure
1 shows representative variably loaded pressure-volume loops from one dog at baseline and with the
highest ADM infusion rate. Figure 1 demonstrates the increase in the
slope of the end-systolic pressure-volume relationship with ADM
administration at the
200-ng · kg1 · min1 dose into the
LV. However, because of the marked decrease in systolic pressure with
the cumulative dose of ADM, there was relatively little overlap in the
end-systolic pressures at which the slopes of the end-systolic
pressure-volume relationships were compared.
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Normal dogs with high-dose ADM only.
The results of the infusion of ADM at 200 ng · kg1 · min1 into the LV, given
without other preceding doses and in closer temporal proximity to
-blockade, are shown in Table
3.
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and
Ees were also unchanged. Representative
pressure-volume loops at baseline and with ADM infusion are shown in
Fig. 2; no change in the slope of the
end-systolic pressure-volume relationship is seen with ADM infusion,
and there is good overlap of the end-systolic pressures at which the
slopes of the end-systolic pressure-volume relationships are compared.
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Heart-failure dogs.
After the induction of heart failure by rapid ventricular pacing,
baseline LV peak systolic pressure and end-systolic pressure were
decreased compared with baseline in normal dogs, and end-diastolic pressure was increased (P < 0.05 for all; Tables 3 and
4).
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1 · min1 into the LV in
pacing-induced heart failure are shown in Table 4.
None of the hemodynamic variables measured changed significantly with
ADM infusion. The changes from baseline in end-systolic pressure and
Ea with ADM infusion were significantly less in
the heart-failure dogs than in the normal dogs studied with the single dose of ADM (P < 0.05 for both).
Figure 3 shows pressure-volume loops from
a dog with pacing-induced heart failure at baseline and with ADM
infusion. No significant change in the slope of the end-systolic
pressure-volume relationship is seen with ADM infusion, suggesting no
inotropic effect.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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These studies are the first to address in vivo the direct myocardial actions of ADM infusion. The results confirm the arterial vasodilating actions of ADM at pathophysiological and pharmacological doses and suggest that these actions are attenuated in heart failure. ADM was without effect on preload and diastolic function and did not demonstrate inotropic actions in normal or heart-failure dogs.
In the first group of normal dogs, only the last and highest dose of
ADM infused into the LV resulted in an increase in
Ees, a relatively load-insensitive measure of
myocardial contractility. However, a number of factors other than a
direct inotropic response are likely to explain the observed increase
in Ees. An increase in heart rate (above the
atrial pacing level) and an increase in plasma norepinephrine were
observed with this highest dose of ADM and suggested reflex sympathetic
activation. Although these studies were conducted in the presence of
-blockade, marked sympathetic activation may have overcome the
competitive blockade of the -adrenergic receptor. The effect of
sympathetic activation and a treppe effect from increased heart rate
may have explained the positive inotropic response observed with the
highest dose. In addition, the end-systolic pressure-volume
relationship can have significant curvilinearity in the range of
pressures observed in normal conscious dogs, and caution is necessary
if pressure-volume relationships are compared over markedly different
pressure ranges, as was the case at the highest dose of this prolonged
(>90 min) infusion (2, 13). Finally, no dose-response
effect of ADM on Ees was observed, and this also
suggests that a direct inotropic effect is unlikely. Therefore, we made
an effort to control these factors in the additional group of five
normal dogs studied with the highest dose of ADM alone. In these dogs,
no inotropic response was observed.
In vitro studies have reported both positive and negative inotropic effects of ADM (8, 28, 29). Differences in experimental design may explain the contradictory results in these studies. Positive inotropic responses independent of cAMP were noted by Szokodi et al. (28, 29) in isolated perfused hearts, whereas Ikenouchi et al. (8) noted a negative inotropic effect in isolated myocytes that was at least partially mediated by nitric oxide. Our results suggest that, in vivo, ADM is without inotropic effects, even at doses that achieve pharmacological plasma ADM concentrations in normal and heart-failure dogs.
A small decrease in was seen with the highest dose of ADM in the
first group of normal dogs receiving the three doses of ADM. This
measure of LV relaxation is sensitive to afterload, sympathetic tone,
and changes in heart rate. Thus the effects of any intervention on need to be interpreted in light of the changes in these parameters
(5). In the normal dogs studied only with the highest dose
of ADM, in which decreases in systolic pressure tended to be lower and
heart rate was unchanged, no effect on was seen. This lack of
effect on diastolic function was also noted in heart failure.
Importantly, in the absence of a specific ADM antagonist, our results obtained in normal dogs and extending to a model of heart failure provide the most direct evaluation of the myocardial actions of ADM in vivo. Previous in vivo studies have reported changes in such variables as maximum rate of change of aortic flow and cardiac output, but these variables are not reliable measures of contractility, being influenced by changes in loading conditions and heart rate (3, 22). No previous studies have reported the effects of ADM on diastolic function.
The vasodilator action of ADM is well established. We noted a dose-dependent decrease in systolic pressure in the normal dogs and a significant decrease in Ea with the highest dose of ADM. However, this action appears to be significantly attenuated in heart failure. These results are in keeping with a study of the vasodilatory effects of ADM in skeletal muscle arteries in normal and heart-failure subjects (21). In that study, the vasodilatory effect was to some extent mediated by nitric oxide, and impaired production of nitric oxide in heart failure may explain some of the attenuated effect. Our results also suggest that ADM is predominantly an arterial vasodilator, as we did not observe changes in variables reflecting preload such as LV end-systolic volume and pressure.
The pathophysiological importance of the elevated ADM plasma concentrations observed in heart failure is currently unclear, although these increased concentrations are of prognostic significance. The current study reports significant hemodynamic effects of ADM infusion at the lowest dose in normal dogs. The plasma concentrations achieved with this dose are in the range of those observed in dogs with experimental heart failure and suggest that these concentrations are pathophysiologically relevant (10). We infused a high dose of ADM in dogs with heart failure and observed no hemodynamic effects; in heart failure, the effects of ADM may be limited by activation of counter-regulatory vasoconstrictor systems. Definitive statements on the pathophysiological significance of circulating ADM in heart failure await the development of a specific antagonist.
We do not address the mechanism of action of ADM. In vitro and in vivo
studies have suggested that cAMP-independent mechanisms mediated via
activation of protein kinase C and nitric oxide may be important
(21, 29). The small increase in cAMP seen in our study
would also be consistent with cAMP-independent mechanisms playing a
major role in the inotropic and other hemodynamic effects of ADM. In
addition, the lack of lusitropic effect would support non-cAMP pathways
mediating the effects observed, as increases in cAMP produced by
-adrenergic agonists or phosphodiesterase inhibitors are associated
with decreases in (7, 19).
In conclusion, although definitive elucidation of the importance of this peptide in the regulation of myocardial function awaits the development of a specific antagonist, this study provides a comprehensive assessment of the myocardial and load-altering actions of ADM in normal and heart-failure dogs. Our results confirm that ADM is an arterial vasodilator but that this action is attenuated in heart failure and that in vivo ADM does not have inotropic actions and is without effect on preload or LV relaxation.
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ACKNOWLEDGEMENTS |
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We thank Denise Heublein and Gail Harty for expert technical assistance.
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FOOTNOTES |
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This work was supported by a National American Heart Association Grant-in-Aid, the Miami Heart Research Institute, the Joseph P. and Jeanne M. Sullivan Foundation, and the Mayo Foundation. J. G. Lainchbury was supported by a Health Research Council of New Zealand Training Fellowship in Clinical Research.
Address for reprint requests and other correspondence: M. M. Redfield, Cardiorenal Research Laboratory, Guggenheim 915, Mayo Clinic and Foundation, 200 First St. SW, Rochester, MN 55905 (E-mail: redfield.margaret{at}mayo.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 22 November 1999; accepted in final form 28 March 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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 C. Y.T. Hart, D. M. Meyer, H. D. Tazelaar, J. P. Grande, J. C. Burnett Jr, P. R. Housmans, and M. M. Redfield Load Versus Humoral Activation in the Genesis of Early Hypertensive Heart Disease Circulation, July 10, 2001; 104(2): 215 - 220. [Abstract] [Full Text] [PDF]
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